REVIEW ARTICLE

Microtubule dynamics in cytoskeleton, neurodegenerative and psychiatric disease

Simone MORTAL*

Neuroscience Area, International School for Advanced Studies (SISSA), 34136 Trieste, Italy

*Correspondence: [email protected] https://doi.org/10.37175/stemedicine.v2i6.81

ABSTRACT (MTs) are fundamental polymers composed by α and β , they provide integrity to neuronal cell and are necessaries in intracellular trafficking and organization. The extension and retraction of MTs occur with the addition or removal of α and β tubulin subunits and the binding with associated proteins (MAPs) that selectively target specific tubulin regions, manipulating the MT dynamics and function. Altered MT homeostasis can compromise the function of MTs in the structural integrity and axonal transport inside the neuron. Here I review the evidence of MT anomalies in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and traumatic brain injury and psychiatric disorders, such as depression, schizophrenia, and bipolar disorder. The focus of this review is to point out which can be the impact of MT issues in the major neurodegenerative diseases and discuss which MT abnormalities can lead to psychiatric illnesses.

Keywords: Microtubules · MAPs · Alzheimer’s disease · Amyotrophic lateral sclerosis · Schizophrenia · Psychiatric disorders · Neurodegenerative diseases

Introduction In this review I examine how MTs are built, and which During the neuronal development stages, aside from are the major proteins that interact with them. Then I the actin cytoskeleton, the assembly, organization and analyse some of the most important neurodegenerative remodelling of the microtubule (MT) cytoskeleton is disorders exploring the interaction that connects disease essential (1–3). MTs compose the rails for intracellular with MT cytoskeleton. In the last part I discuss how transport, they can act as signalling devices, generate anomalies in the MTs, or related proteins, can lead to cellular forces and mediate vesicular release (4–7). psychiatric disease. The MT cytoskeleton is fundamental in neuronal development, this is highlighted by the wide range of nervous system abnormalities and several human Microtubule organization neurodevelopmental disorders linked to altered MT- The MT structure is built from heterodimers of α and β mediated processes. In addition, there are several tubulin, that are bound in a head to tail relation to form developmental problems that can be linked to mutations in polarized structures; these associate laterally to form a MT-related genes that encode for microtubule-associated hollow tube, with a diameter of 25 nm (5). MTs are very proteins (MAPs), MT motor associated regulators or MT dynamic structures, that continuously switch between severing proteins (8,9). elongation and disassembly, in a process called dynamic instability; this procedure allows individual MT to explore cellular regions and to retract if it does not find the proper Received: Feb 8, 2021; Accepted: Mar 22, 2021. environment (10). MT function and dynamics are regulated by the © The Author(s). 2020 This is an Open Access article distributed under the terms of the properties of tubulin; the free tubulin binds GTP, which is Creative Commons License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the hydrolysed after being incorporated into the MT structure. original work is properly cited. The growth of the MT is promoted by the GTP cap, in

1 MORTAL STEMedicine 2(6).e81. APR 2021 fact, GDP-tubulin tends to destabilize the MT architecture, processes and translocate the nucleus into this processe. consequently stable growth is believed to depend on the These movements are driven by actin and MTs filaments, presence of a GTP-tubulin cap at the MT plus end (11). In the first promotes neuronal migration by propulsive this model, the loss of the cap will result in a collapse of contractions at the cell rear and MTs which are anchored the structure, called catastrophe (12). to the centrosome extend the leading process and form At the end of the MT there is a minus end and a plus a cage-like structure around the nucleus. Cytoskeletal end, these ends can grow and depolymerize, but these forces in the leading edge can pull the centrosome into the two dynamics are completely different. Minus ends are proximal part of the leading process and move the nucleus stabilizes by minus end tracking proteins (-TIPs), they in the direction of cell migration (22). grow more slowly and undergoes catastrophe less rarely, Neurite initiation and outgrowth begins with the not a lot is known about them, in fact they start to emerge breakage of the circular shape of new-born neurons by recently (13). The plus end, terminate with β-tubulin, emerging neurites. These newborn neurites are composed grows with polymerization of the subunits, undergoes by bundled MTs and a growth cone which mediates the catastrophe more frequently and is a crucial site for pushing and pulling forces that provide to membrane regulating MT dynamics (14). protrusion (23,24). Plus end tracking proteins (+TIPs) concentrate at the MT stabilization plays a fundamental role in axon ends of growing MTs and control different aspects of its differentiation during the neuronal polarization. The progress, like recruiting tubulin dimers and increasing the increased MTs stability leads to kinesin mediated flow rate of tubulin addition to growing tips (15). Nevertheless, and contributes to determining the future axon formation. the polymerization of microtubule based structures not The complete mechanism of axon differentiation only depends on +TIPs, but also requires many other remains unknown, but internal signals, like centrosome factors, like MAPs, motor proteins and tubulin isotypes (5). localization, Golgi position and cytoskeleton architecture, Concentrating on the different ways of action, five groups could introduce a local imbalance inside the MT network of proteins can be assumed from the microtubule related that leads to stabilize MTs in only one of the many proteins. Firstly, proteins that bind to the MT ends and neurites (25,26). can regulate their dynamics, this group contains the +TIPs During axonal elongation the MT cytoskeleton and minus end targeting proteins (-TIPs) (5,14). Then, participates in functional interactions with actin and the group of proteins that bindS to the MT lattice and can adhesion complex, that with +TIPs can modulate the stabilize or crosslink MTs (16,17). The third group includes MT properties and stability (25). In addition to MT proteins that modulate the MT abundance, enzymes that polymerization, recent studies found that the translocation sever MTs and regulators of the nucleation (18,19). The of whole MT bundles into the axon contribute to axon fourth group contains the kinesin and dynein families that elongation, that is presumably generated by molecular generate forces and move directionally along MTs (20). motors (27,28). The last group comprises tubulin folding cofactors and Dendritic spine morpho dynamic and synapse functioning tubulin modifying enzymes that can generate distinct MT are linked directly to MT dynamics, in fact, evidences subtypes through post translational modifications (21) suggest that MTs are associated with transient changes (Figure 1). in spinal shape, such as the formation and enlargement of the spine. MTs that entered into spines are regulated The Neuronal MT Cytoskeleton by the neuronal activity and brain derived neurotrophic The MTs of neurons are involved in the morphological factor (BDNF), these MTs with MT dependent motors are changes during the different phases during their responsible to drive postsynaptic cargoes into spines (29). development, in the intracellular transport and during MTs cytoskeleton is organized in bundles and axonal synapse growth. cross sections are usually composed by 10-100 MTs. In Neurons need to have an active and efficient transport several cell types, MTs are nucleated at the microtubule mechanism, to properly distribute many cellular organizing centre (MTOC), such as the centrosome, but components and establish signalling pathways. The they can be generated even in other different places, such motor protein families that play this role are Kynesins as the Golgi apparatus or along existing MTs, where not and dyneins, they travel along the neuronal MTs carrying all the minus ends are directed towards the MTOC (30,31). many types of neuronal cargo: neurotransmitter receptors, In new-born neurons the centrosome first acts as an active synaptic vesicles, cell adhesion molecules, organelles, MTOC, but with time this activity is completely lost. cell signalling molecules and mRNAs. In addition, Super resolution studies and electron microscopy have cargo adaptor proteins, regulatory molecules and MT shown that MTs are not anchored to the centrosome and cytoskeleton have an important role in the delivering of often in mature neurons there are free ends (Figure 2). different cargos in the correct location (20). Because most MTs do not emerge from MTOC, their MTs are fundamental in the morphological transitions relative orientations can be different. Electron microscopy that occur during neuronal development: the neurite with hook decoration technique showed that MTs initiation, migration, polarization and differentiation. orientations in axons and dendrites have two different Neuronal migration is a complex sequence of motile and patterns (32). In axons is possible to observe uniformly morphogenetic events, in which neurons extend primary plus end out oriented MTs, while in proximal dendrites

https://doi.org/10.37175/stemedicine.v2i6.81 2 MORTAL STEMedicine 2(6).e81. APR 2021

Figure 1. The cartoon illustrates different MAPs that interact with the MT.

the MTs orientations are non-uniformly, in fact MTs are microtubule structure, increase the MTOC-independent half plus end out and half minus end out oriented. microtubule polymerization and is a cross-linker of This different distribution in MTs orientation contributes tubulin filaments (46,47). Reduced levels of MAP2, can to the differential trafficking in axons or dendrites (33). be compensate by MAP1b, but the deletion of both genes The selective presence of minus end out oriented in leads to perinatal lethality (47). dendrites allow dyneins to selectively transport cargoes Several different MAPs can potentially coexist on one in dendrites. On the other hand, kinesin 1 has been shown MTs and a big number of binding sites are present on the to selectively transport cargoes into the axon, where MTs microtubule surface. MAPs bind the microtubules for are composed by almost all plus end out oriented (25,34). different functions, like binding with specific proteins or This separation of duties is possible because kinesin move cross linking of different MTs. Although a common effect along the MTs towards the plus end while dynein move to of several MAPs is to reduced microtubule tendency the minus end (35). to depolymerize, however is important to remember that MAPs are not merely sticked to MTs, but they Microtubule Associated Proteins dynamically bind and unbind MTs. The microtubule dynamics cannot be efficient and determined only by polymerized tubulin, but need specific Microtubules in Neurodegeneration proteins that interacts with tubulin – the microtubule Several neurodegenerative disorders are characterized by associated proteins (MAPs). Depending on their role, altered axonal transport, that can cause neuronal damages MAPs can be categorized into motile MAPs, motor and death. Though different causes can contribute to proteins that generate movements and forces (36,37); damage the axonal transport, in many cases appear that enzymes that cut or depolymerize tubulin (38); nucleators transport deficits result from reduced MT stability (48). (39); end-binding proteins that bind the minus or plus Here, I review evidences of MT instability in some of ends of microtubules (13); and the structural MAPs. the most common neurodegenerative disease, such as While, the first four categories of MAPs are well defined Alzheimer’s Disease, Parkinson’s Disease, traumatic brain by their functions, the last group bind microtubules to injury and amyotrophic lateral sclerosis. stabilize them, but there is not a clear and broad view on their functions (40). Microtubules dysfunction in Alzheimer’s Disease and Structural MAPs are a large category, that includes Tauopathies different proteins all able to decorate the MT cytoskeleton, Tauopathies are neurodegenerative disorders but only some of them, such as tau, induce microtubule characterized by the deposition of insoluble fibrils of bundling (41,42). A possible mechanism on how MAPs hyperphosphorylated tau, that are called neurofibrillary can directly participate in microtubule bundling was tangles (NFTs) and are localized in the neuronal soma or recently proposed: MAPs are proteins rich in positive dendrites. Alzheimer disease (AD) is the most notorious charged ammino acids, the abundance of this charges disorder among tauopathies, but it is not only due by neutralize the negative charges of the C-terminals of tau, in fact this disorder is a mixed proteinopathy, where (43). This process reduces the electrostatic amyloid beta (Aβ) peptide, α-synuclein and TDP-43 are repulsion between MTs and allow the bundling them. usually involved. In particular, MAP2 is extremely present in brain and Tau protein is thought to play a fundamental role in MT its function is directly related to neuronal plasticity. It has properties and functions: the of multiple isoforms, the high molecular weight (HMW- tau reduces the binding affinity to MT and lead to form MAP2), MAP2A and MAP2B selectively expressed insoluble fibrils. It is believed that Tau - mediated toxicity in neurons and the low molecular weight (LMW- is due to the formation misfolded insoluble fibrils and/ MAP2), MAP2C and MAP2D expressed in neurons and or altered properties of MT that result in a release of tau glia (44,45). MAP2 induce characteristic changes in form MT and a subsequent aggregation into inclusions.

https://doi.org/10.37175/stemedicine.v2i6.81 3 MORTAL STEMedicine 2(6).e81. APR 2021

Figure 2. MT changes during neuronal development. After their final division, neurons transit through many developmental stages and the MT cytoskeleton has a crucial role at all the different stages. The MT cytoskeletal organization changes from a radially centrosome-based with largely plus-end out-oriented network to an acentrosomal network with uniform orientations in the axon and mixed orientation in dendrites.

The contribute of tau loss of function in neurodegeneration dependent trafficking, Golgi fragmentation and neurite of tauopathies, is confirmed by observations of degeneration. Interestingly a possible involvement of reduced number of MT in AD brains and the decreased hyperphosphorylated tau in MT instability was observed concentration of acetylated α-tubulin, that is an hallmark in PD models; with the involvement of kinase LRRK2 of stable MTs. Furthermore, studies on mouse models that is mutated in familiar cases of PD. This protein can for NTFs tauopathies revealed abnormalities in MT, such phosphorylate tau bound to MTs, reducing the binding of as the reduction in MT concentration, the increased MT tau with MTs and increasing the free tau inside the cell dynamicity and reduced axonal transport. These results which can lead to pathology. Furthermore, the increased have led to consider agents that increased MT stability, tau by mutated LRRK2 is probably due to such as drugs for the treatment of cancer (49), as potential an enhanced binding affinity between mutated LRRK2 and candidates for treatment of AD and tauopathies (50). MTs. Moreover, overexpression of LRRK2 in transgenic mouse models with mutation A53T on α-synuclein worsen Traumatic brain injury the pathology and with an acceleration in α-synuclein There are many observations that repetitive traumatic aggregation, that can be due to the damaged dynamics of brain injuries (TBI) (51) induce chronic traumatic MT. Therefore, alterations in MTs stability can cause an encephalopathy (CTE), characterized by behavioural increase of both α-synuclein and tau pathology. anomalies and neuronal loss (52). In particular, brains Lastly decreased MT stability can also come from present neurons with diffuse axonal damage, large mutations on Parkin protein that cause familial PD. breakage of the MT cytoskeleton and the loss of axonal Studies on neurons derived from iPSC fibroblasts of transport (53–55). Interestingly, repeated TBI can lead patients with mutated Parkin protein showed a reduction to develop tau pathology that starts to spread out from in MTs stability and consequently a reduced neurite cortical sulci; this can be explained by the relationship length and arborization. Notably, the altered morphology between tauopathies and reduction of MT stability and of this neurons can be repaired with the administration of axonal transport (53,56). Moreover, TBI can outcome pacilitaxel, a MT stabilizing drug (61). in AD or other neurodegenerative symptoms (57). This However, action of Parkin protein on MT is not fully suggests that MT stabilizing drugs can be effective on the understood and interesting it can interact with HDAC6 (62), neurodegenerative conditions caused by TBI/CTE. On that can deacetylate MTs, but additional studies are needed this way the MT dysfunctions are becoming one of the to investigate the Parking effect on MT. distinctive features of TBI and on the therapy front, good results are coming from MT stabilizers drugs such as Amyotrophic lateral sclerosis epoD and paclitaxel (58–60) Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease of motor neurons (63). Why these Parkinson’s disease neurons seem to be the more vulnerable to ALS is not Parkinson’s disease (PD) is a brain disorder which completely clear, but MT instability and deficient axonal provide locomotor impairments, that is due to the loss transport would be particularly destructive in motor of dopaminergic neurons in the substantia nigra pars neurons that have a morphology with longest axons in compacta. Pathological neurons of this region present intra the body. In this way there are evidences that support neuronal inclusions of α-synuclein called Lewi bodies. As the involvement of defective axonal transport in ALS in AD, there are evidences of MT anomalies in PD brains (64). For example, dynactin is a protein that works in that probably contribute to neurodegeneration. In fact, association with dynein, is very important in retrograde the extensive axonal arborization of the dopaminergic axonal transport, but when mutated in subunit p150glued neurons of substantia nigra because makes this type of can cause motor neuron disease and maybe ALS (65). neurons particularly fragile in case of damaged of axonal Additionally, 10% of hereditary ALS cases present transport. Studies on the relationship between α-synuclein mutations superoxidase dismutase 1 (SOD1) gene, that and MTs revealed that neurons overexpressing participates anterograde mitochondrial transport inaxons α-synuclein present MT dysfunction, compromised MT (66). Experiments on transgenic mouse models with

https://doi.org/10.37175/stemedicine.v2i6.81 4 MORTAL STEMedicine 2(6).e81. APR 2021

SOD1 mutated develop axonal transport deficits before the Tubulin Isotypes onset of the neurodegeneration (67,68). In addition, these During human brain development various tubulin isotypes transgenic mice line present increased MT dynamicity are expressed, the different isotypes can influence the that can be restored on normal levels with noscapine, can structural and interaction properties of the MT and have restore the axonal transport and decrease the MT turnover, different affinity with PMT modifications. In particular with a reduced cell death (69). Moreover, other studies α1A, βII and βIII are the most present tubulin isotypes in the in ALS mouse models confirmed that mutated SOD1 brain, while α1B, α1C, βI and βIVb that are expressed in the increase the MT dynamicity, expanding the evidences that whole body. Altered expression of tubulin isotypes were mutations in SOD1 perturb the MT homeostasis (70,71). identified from proteomic studies in rodent models of As mutated SOD1 concerns a little fraction of ALS depression. It has been noted that isolation rodent models patients, evidence of altered MT dynamics and axonal have a reduction in α-tubulin expression (83) and rats transport are needed in non SOD1 ASL models to genetically sensitive to depression have a huge decrease in support the involvement of MTs in ALS. In this way, βIIA and βV tubulin expression in hippocampus (84). These studies on mouse model for ALS (TDP-43) revealed studies show that reduced α and β tubulin expression that mutations on TDP-43, a DNA binding protein, are in hippocampus is a hallmark of depression in rodents associated with axonal transport problems (72). TDP-43 models. is implicated in ALS, in fact it is the main protein found It is possible to observe decreased tubulin isotypes even in positive inclusions that are characteristic of in humans, for example in patients with schizophrenia ALS pathology. In addition, mouse models TDP-43 have or bipolar disorder have a decreased expression of a reduction in mitochondrial motility, that can appear just β-tubulin isotype in the prefrontal cortex (85). Coherent before the onset of the first symptoms of ALS (73). with this, gene expression analysis from patients with Nevertheless, the molecular mechanisms implicated major depressive disorder, shows that TUBB4 and are not fully understood and further experiments will be TUBB2C isotypes are down-regulated in the dorsolateral necessary to understand the molecular cascade that links prefrontal cortex (86). Taken together these data highlight TDP-43 and SOD1 with MT stability and ALS. that the expression of tubulin isotypes is significantly altered in clinical and animal models of psychiatric Therapeutic Drugs disorders, showing that distorted tubulin homeostasis is a As discussed herein, there are several evidences that characteristic these circumstances. the axonal transport deficit is involved in numerous neurodegenerative disease and this is probably induced Tubulin PTMs by the altered MT stability. In these way MT stabilizing Post translational modifications of tubulin (PTMs) is drugs were identified as potential candidates for treatment a powerful mechanism to generate specific microtubule of neurodegenerative disease. MT stabilizing drugs, as it is identities (87). These modifications which include known, can inhibit the cell division and thus are the ideal /deacetylation, phosphorylation, tyrosination/ drugs to work in CNS and interact with neurons. Recent , glutamylation and polyglycylation create a results with epothiloneD (epoD) a MT stabilizer show unique environment for the interaction of specific MAPs encouraging benefits in mouse models (74). In particular, to the MTs (88). different studies showed the efficacy of epoD in reducing Acetylation/deacetylation. Acetylation can be the MT hyperdinamicity and neuronal loss. This drug is performed on both α and β tubulin residues, where acetyl particularly effective in thaupaties and AD (75–77), but transferase αTAT and Atat-2 act on the former and Sun significant benefits were noted even for TBI and PD (58,78). acetyltransferase work on β-tubulin (88). On the other However, other drugs were studied in mouse models, such hand, deacetylation is performed by histone deacetylase as dictyostatin, this drug have relevant benefits in the CNS, 6 (HDAC6) and nicotine adenine dinucleotide-dependent but complications in the gastrointestinal tract and mortality deacetylase sirtuin-2 (SIRT2) (89). was observed on mouse models (79–82). This show that The role of HDAC inhibitors as antidepressants is well not all MT stabilizing drugs are equal, and that carefulness known and it was largely tested on rodent models of and further studies will be necessary to guarantee benefits depression (90). On this way, behavioural studies conducted without major side effects. on HDAC6 Knockout (KO) mice revealed that these mice express low anxiety, hyperactivity and low depressive phenotype (91). Furthermore, reduced expression of SIRT2 Microtubules in Psychiatric Disease deacetylase is characteristic in rodent models of depression, Cytoskeleton dysfunctions have been observed even in suggesting that this deacetylase protein can be directly several neuropsychiatric disorders such as schizophrenia, implicated in depressive behaviour (92). major depressive disorder (MDD) and bipolar disorder. Reduced levels of tubulin acetylation have been observed The hypothesis that altered MT dynamics leads to a even in rats after social isolation (83), while they are disrupted synaptic connectivity is supported by clinical increased in the hippocampus of rats after exposure to studies and animal models. Here, I present some findings unpredictable chronic mild stress (93). Tubulin acetylation that connects altered MTs homeostasis with psychiatric is also diminished after knockdown of Ulk4 (Unc-51 diseases. like kinase-4), a gene that has been funded deleted in

https://doi.org/10.37175/stemedicine.v2i6.81 5 MORTAL STEMedicine 2(6).e81. APR 2021 schizophrenia and bipolar disorders(94). Mouse models MAPs in Psychiatric Disorders with Ulk4 knockdown have reduced neurite length, Dendritic arborization and spine density is directly diminished branching, and agenesis of the corpus related with MAPs (29), in fact reduced levels of these callosum. Interestingly also, c-Jun NH2-terminal protein can lead to neurological disease (107,108), intellectual kinase (JNK) activity is reduced in these Ulk4 knockdown disability (109), depression (110,111) and schizophrenia mice (95). JNK is a protein that regulate the MT (108). In case of depression the synapse loss damages the homeostasis and neurite complexity and it can represent a feedback loops and the adaptive response for stress (112). possible link between Ulk4 and MT integrity. Spine loss in schizophrenia is associated with reduced All these findings suggest that tubulin acetylation levels MAP2 (113), suggesting a participation in the spine are altered in models of schizophrenia and depression. stabilization, suggesting a role for MT in in spine head This can be the cause of abnormalities in the development stability. Crucial for synaptic disorders is also how MAP2 of axons and dendrites and synaptic plasticity. impact on CREB activity by binding PKA in dendrites Furthermore, kinases implicated in schizophrenia have (114). CREB controls the expression of BDNF, that is a role in the pathway that controls MT stabilization, fundamental in synapse and neuronal survival. suggesting a link between pathological symptoms and the loss of cytoskeletal homeostasis. Loss of MAP2 immunoreactivity is an hallmark of Phosphorylation. The addition of a phosphate group schizophrenia results in a gain of negative charges that change the In the last twenty years several studies were conducted chemical properties of tubulin. Phosphorylation is post-mortem on schizophrenia patients and a common performed on neuronal βIII tubulin and on α-tubulin, feature of the analysed brains were the reduced this mechanism is particularly active during neuronal immunoreactivity of MAP2 (113). This was localized differentiation and helps the microtubule polymerization specifically in hippocampus and prefrontal cortex where (96–98). Phosphorylation of tubulin induces it coincides with diminished dendrite ramification. The conformational changes of MT, this can change the reduced immunoreactivity noted does not mean reduced binding site for stabilizing drugs used in psychiatric MAP2, in fact proteomic analysis on schizophrenic disease such as valproate lithium and paliperidone, or depressed patients show no altered levels of MAP2 implying that this modifications are relevant in pathologies protein (85). Consistent with this MAP2 mRNA is not (99). altered in patients with schizophrenia (115), but the Tyrosination/detyrosination. Tyrosination is performed decreased immunoreactivity seems due to PTM of MAP2 by tubulin ligase (TTL) on α-tubulin; (e.g., phosphorylation), that limit the epitope recognition. tyrosinated tubulin increase microtubule dynamics while This modification probably can lead to an altered function detyrosination enhance microtubule stability, these of MAP2 and contribute to the typical disorders of dynamics are important in axonal extension and transport psychiatric disease. (88). Detyrosination concerns the removal of Tyr from the C-terminal of α-tubulin to expose a Glu residue. In this MAP6 way, Glutamylation is done by tubulin tyrosine ligase- Like MAP2, MAP6 stabilizes microtubules, binding like (TTLL), that add chains of glutamates to the carboxy together the nearby microtubules (116,117). Mice terminal of tubulin. This happens at high levels usually in MAP6 KO present severe symptoms associated with brain. influence the surface charges on schizophrenia, that can be anxiety, impaired cognition, MTs modifying the binding properties to MAPs and motor hyperactivity and social withdrawal (118). In particular, proteins (100). It is known that damaged protein transport MAP6 deletion damage the cognitive function damaging and the compromised binding of MAPs can contribute to the synaptic connectivity (118,119). Studies on post- pathology in schizophrenia (101). In fact, problems on the mortem brains evidence that mRNA MAP6 levels TTLL11 ployglutamylase gene are linked to schizophrenia are improved in prefrontal cortex of patients with and bipolar disorder (102,103). schizophrenia. These studies together suggest an Polyglycylation. This modification is peculiar of cilia involvement of MAP6 with the onset of the schizophrenia and flagella. It can be present on α and β tubulin and (120), but further study will be necessary to point out the the responsible enzymes are the members of the TTL molecular mechanism. family (104). Glycylation is important in stabilization and motility of ependymal cilia which plate ventricles of the Therapeutic Drugs brain (105), but it is interesting to note that in cilia effects These studies indicate that microtubule regulators of diverse neuropsychiatric risk genes converge (106). and PTM of MAPs are altered in psychiatric disorders. Some effects of these modifications can be rescued by MAPs the treatment with antidepressant drugs, neurosteroids MAPs are fine regulators of the microtubule properties like microtubule associated protein neurosteroidal and function in neuronal network; therefore an pregnenolone (MAPREG), pregnenolone (PREG) imperfect function of these proteins can give rise to and dehydroepiandrosterone (DHEA) were noticed to neurodegenerative, developmental and psychiatric enhance the neuronal survival and improve long term disorders (29). memory (121). Binding of these neurosteroids that are

https://doi.org/10.37175/stemedicine.v2i6.81 6 MORTAL STEMedicine 2(6).e81. APR 2021 synthetized in multiple glial cells (122,123), promotes of cortical development and neurodegenerative diseases. the neurite growth stimulating the MAP2 effect on MT Biochem Soc Trans. 2013;41(6):1605–12. polymerization (123–126). Neurosteroids improve the 9. Reiner O, Sapir T. LIS1 functions in normal development and disease. Curr Opin Neurobiol. 2013;23(6):951–6. neuronal survival and have a neuroprotective effect, they 10. Howard J, Hyman AA. Growth, fluctuation and switching can even stimulate neurogenesis in adult hippocampus at microtubule plus ends. Nat Rev Mol Cell Biol. agosto improving the long term memory (127–129). 2009;10(8):569–74. On the other hand, were noted that MT drugs have 11. Alushin GM, Lander GC, Kellogg EH, Zhang R, Baker D, significant benefits on behaviour. In particular, lithium Nogales E. High-resolution microtubule structures reveal the structural transitions in αβ-tubulin upon GTP hydrolysis. Cell. is a mood stabilizing drug used to treat bipolar disorder 2014;157(5):1117–29. (130,131). Studies revealed that the administration 12. Brouhard GJ, Rice LM. Microtubule dynamics: an interplay of lithium directly inhibit GSK-3, this reduces the of biochemistry and mechanics. Nat Rev Mol Cell Biol. phosphorylation of tau and MAP1B protein leading to MT 2018;19(7):451–63. remodelling (132–134). Modification of the cytoskeleton 13. Akhmanova A, Steinmetz MO. Control of microtubule organization and dynamics: two ends in the limelight. Nat structure may help to stimulate the neuroplasticity in Rev Mol Cell Biol. 2015;16(12):711–26. the brain areas interested by the mood disorder like 14. Akhmanova A, Hoogenraad CC. Microtubule minus-end- hippocampus and amygdala (135). targeting proteins. Curr Biol. 2015;25(4):R162–71. 15. Akhmanova A, Hoogenraad CC. Microtubule plus-end- tracking proteins: mechanisms and functions. Curr Opin Cell Conclusions Biol. 2005;17(1):47–54. As discussed herein, there is a convincing number of 16. Dehmelt L, Halpain S. The MAP2/Tau family of microtubule- evidences that axonal transport troubles are involved in associated proteins. Genome Biol. 2004;6(1):204. several neurodegenerative and neuropsychiatric disease. 17. Subramanian R, Kapoor TM. Building complexity: insights This issues in transport can be due in part or whole to into self-organized assembly of microtubule-based architectures. Dev Cell. 2012;23(5):874–85. the perturbed MT homeostasis, increase or decrease of 18. Kollman JM, Merdes A, Mourey L, Agard DA. Microtubule microtubule stability. The focus of this review has been nucleation by γ-tubulin complexes. Nat Rev Mol Cell Biol. on how MT variations can alter axonal transport and there 2011;12(11):709–21. is a growing number of studies regarding MT defects 19. Sharp DJ, Ross JL. Microtubule-severing enzymes at the in cell cultures or animal models of neurodegenerative cutting edge. J Cell Sci. 2012;125(11):2561–9. 20. Hirokawa N, Niwa S, Tanaka Y. Molecular motors in or psychiatric disease. These observations have led to neurons: transport mechanisms and roles in brain function, experiment MT stabilizing drugs, usually used in the development, and disease. Neuron. 2010;68(4):610–38. treatment of cancer, on animal models of disease with 21. Hammond JW, Huang C-F, Kaech S, Jacobson C, Banker good results. The challenge now is to develop and test new G, Verhey KJ. Posttranslational modifications of tubulin and drugs that can support the treatment of neurodegenerative the polarized transport of kinesin-1 in neurons. Mol Biol Cell. 2010;21(4):572–83. or psychiatric disease in human patients. 22. Cooper JA. Cell biology in neuroscience: mechanisms of cell migration in the nervous system. J Cell Biol. 2013;202(5):725-34. 23. Cáceres A, Ye B, Dotti CG. Neuronal polarity: demarcation, growth and commitment. Curr Opin Cell Biol. Conflict of interest The authors declare that there is no conflict of interests regarding 2012;24(4):547–53. the publication of this paper. 24. Flynn KC, Hellal F, Neukirchen D, Jacob S, Tahirovic S, Dupraz S, et al. ADF/Cofilin-mediated actin retrograde flow directs neurite formation in the developing brain. Neuron. 2012;76(6):1091–107. References 25. Nakata T, Hirokawa N. Microtubules provide directional 1. Coles CH, Bradke F. Coordinating neuronal actin– cues for polarized axonal transport through interaction with microtubule dynamics. Curr Biol. 2015;25(15):R677–91. kinesin motor head. J Cell Biol. 2003;162(6):1045–55. 2. Sainath R, Gallo G. Cytoskeletal and signaling mechanisms 26. Nakata T, Niwa S, Okada Y, Perez F, Hirokawa N. of neurite formation. Cell Tissue Res. 2015;359(1):267–78. Preferential binding of a kinesin-1 motor to GTP-tubulin–rich 3. Mortal S, Iseppon F, Perissinotto A, D’Este E, Cojoc D, microtubules underlies polarized vesicle transport. The J Napolitano LMR, et al. Actin waves do not boost neurite Cell Biol. 2011;194(2):245–55. outgrowth in the early stages of neuron maturation. Front 27. Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Cell Neurosci. 2017;11:402. Umlauf M, et al. Microtubule stabilization reduces scarring 4. Howard J. Molecular motors: structural adaptations to and causes axon regeneration after spinal cord injury. cellular functions. Nature. 1997;389(6651):561–7. Science. 2011;331(6019):928–31. 5. Akhmanova A, Steinmetz MO. Tracking the ends: a dynamic 28. Ruschel J, Hellal F, Flynn KC, Dupraz S, Elliott DA, Tedeschi protein network controls the fate of microtubule tips. Nat Rev A, et al. Systemic administration of epothilone B promotes Mol Cell Biol. 2008;9(4):309–22. axon regeneration after spinal cord injury. Science. 6. Barnes AP, Polleux F. Establishment of axon-dendrite 2015;348(6232):347–52. polarity in developing neurons. Annu Rev Neurosci. 29. Hoogenraad CC, Bradke F. Control of neuronal polarity and 2009;32:347-81. plasticity – a renaissance for microtubules? Trends Cell Biol. 7. Kuijpers M, Hoogenraad CC. Centrosomes, microtubules 2009;19(12):669–76. and neuronal development. Mol Cell Neurosci. 30. Bettencourt-Dias M, Glover DM. Centrosome biogenesis 2011;48(4):349–58. and function: centrosomics brings new understanding. Nat 8. Lipka J, Kuijpers M, Jaworski J, Hoogenraad CC. Mutations Rev Mol Cell Biol. 2007;8(6):451-63. in cytoplasmic dynein and its regulators cause malformations 31. Kapitein LC, Hoogenraad CC. Building the neuronal

https://doi.org/10.37175/stemedicine.v2i6.81 7 MORTAL STEMedicine 2(6).e81. APR 2021

microtubule cytoskeleton. Neuron. 2015;87(3):492–506. A review. Rehabil Res Pract. 2012;2012:816069. 32. Baas PW, Lin S. Hooks and comets: The story of 53. Johnson VE, Stewart W, Smith DH. Axonal pathology in microtubule polarity orientation in the neuron. Dev Neurobiol. traumatic brain injury. Exp Neurol. 2013;246:35–43. 2011;71(6):403–18. 54. Tang-Schomer MD, Johnson VE, Baas PW, Stewart W, 33. Kapitein LC, Hoogenraad CC. Which way to go? Smith DH. Partial interruption of axonal transport due to Cytoskeletal organization and polarized transport in neurons. microtubule breakage accounts for the formation of periodic Mol Cell Neurosci. 2011;46(1):9–20. varicosities after traumatic axonal injury. Exp Neurol. 34. Kapitein LC, Schlager MA, Kuijpers M, Wulf PS, van 2012;233(1):364–72. Spronsen M, MacKintosh FC, et al. Mixed microtubules 55. Tang-Schomer MD, Patel AR, Baas PW, Smith DH. steer dynein-driven cargo transport into dendrites. Curr Biol. Mechanical breaking of microtubules in axons during 2010;20(4):290–9. dynamic stretch injury underlies delayed elasticity, 35. Lu W, Gelfand VI. Moonlighting motors: kinesin, dynein, and microtubule disassembly, and axon degeneration. FASEB J. cell polarity. Trends Cell Biol. 2017;27(7):505–14. 2010;24(5):1401–10. 36. Hirokawa N, Noda Y, Tanaka Y, Niwa S. Kinesin superfamily 56. McKee AC, Alosco ML, Huber BR. Repetitive head impacts motor proteins and intracellular transport. Nat Rev Mol Cell and chronic traumatic encephalopathy. Neurosurg Clin N Biol. 2009;10(10):682–96. Am. 2016;27(4):529–35. 37. Bhabha G, Johnson GT, Schroeder CM, Vale RD. How 57. Gardner A, Iverson GL, McCrory P. Chronic traumatic dynein moves along microtubules. Trends Biochem Sci. encephalopathy in sport: a systematic review. Br J Sports 2016;41(1):94–105. Med. 2014;48(2):84–90. 38. McNally FJ, Roll-Mecak A. Microtubule-severing enzymes: 58. Brizuela M, Blizzard CA, Chuckowree JA, Dawkins E, From cellular functions to molecular mechanism. J Cell Biol. Gasperini RJ, Young KM, et al. The microtubule-stabilizing 2018;217(12):4057–69. drug Epothilone D increases axonal sprouting following 39. Roostalu J, Surrey T. Microtubule nucleation: beyond the transection injury in vitro. Mol Cell Neurosci. 2015;66:129–40. template. Nat Rev Mol Cell Biol. 2017;18(11):702–10. 59. Cross DJ, Garwin GG, Cline MM, Richards TL, Yarnykh 40. Bodakuntla S, Jijumon AS, Villablanca C, Gonzalez-Billault V, Mourad PD, et al. Paclitaxel improves outcome from C, Janke C. Microtubule-associated proteins: structuring the traumatic brain injury. Brain Res. 2015;1618:299–308. cytoskeleton. Trends Cell Biol. 2019;29(10):804–19. 60. Chuckowree JA, Zhu Z, Brizuela M, Lee KM, Blizzard CA, 41. Kanai Y, Takemura R, Oshima T, Mori H, Ihara Y, Dickson TC. The microtubule-modulating drug Epothilone D Yanagisawa M, et al. Expression of multiple tau isoforms alters dendritic spine morphology in a mouse model of mild and microtubule bundle formation in fibroblasts transfected traumatic brain injury. Front Cell Neurosci. 2018;12:223. with a single tau cDNA. J Cell Biol. 1989;109(3):1173–84. 61. Ren Y, Jiang H, Hu Z, Fan K, Wang J, Janoschka S, et 42. Barlow S, Gonzalez-Garay ML, West RR, Olmsted JB, al. Parkin mutations reduce the complexity of neuronal Cabral F. Stable expression of heterologous microtubule- processes in iPSC-derived human neurons. Stem Cells. associated proteins (MAPs) in Chinese hamster ovary 2015;33(1):68–78. cells: evidence for differing roles of MAPs in microtubule 62. Jiang Q, Ren Y, Feng J. Direct binding with histone organization. J Cell Biol. 1994;126(4):1017–29. deacetylase 6 mediates the reversible recruitment of parkin 43. Wang Q, Crevenna AH, Kunze I, Mizuno N. Structural basis to the centrosome. J Neurosci. 2008;28(48):12993–3002. for the extended CAP-Gly domains of p150glued binding to 63. Masrori P, Damme PV. Amyotrophic lateral sclerosis: a microtubules and the implication for tubulin dynamics. Proc clinical review. Eur J Neurol. 2020;27(10):1918–29. Natl Acad Sci U S A. 2014;111(31):11347–52. 64. Bercier V, Hubbard JM, Fidelin K, Duroure K, Auer TO, 44. Kalcheva N, Albala J, O’Guin K, Rubino H, Garner C, Shafit- Revenu C, et al. Dynactin1 depletion leads to neuromuscular Zagardo B. Genomic structure of human microtubule- synapse instability and functional abnormalities. Mol associated protein 2 (MAP-2) and characterization of Neurodegener. 2019;14(1):27. additional MAP-2 isoforms. Proc Natl Acad Sci U S A. 65. Puls I, Jonnakuty C, LaMonte BH, Holzbaur ELF, Tokito M, 1995;92(24):10894–8. Mann E, et al. Mutant dynactin in motor neuron disease. Nat 45. Matsunaga W, Miyata S, Kiyohara T. Redistribution of MAP2 Genet. 2003;33(4):455–6. immunoreactivity in the neurohypophysial astrocytes of adult 66. Moller A, Bauer CS, Cohen RN, Webster CP, De Vos KJ. rats during dehydration. Brain Res. 1999;829(1–2):7–17. Amyotrophic lateral sclerosis-associated mutant SOD1 46. Al-Bassam J, Ozer RS, Safer D, Halpain S, Milligan RA. inhibits anterograde axonal transport of mitochondria by MAP2 and tau bind longitudinally along the outer ridges of reducing Miro1 levels. Hum Mol Genet. 2017;26(23):4668–79. microtubule protofilaments. J Cell Biol. 2002;157(7):1187–96. 67. Zhang B, Tu P, Abtahian F, Trojanowski JQ, Lee VM-Y. 47. Teng J, Takei Y, Harada A, Nakata T, Chen J, Hirokawa Neurofilaments and orthograde transport are reduced in ventral N. Synergistic effects of MAP2 and MAP1B knockout in root axons of transgenic mice that express human SOD1 with neuronal migration, dendritic outgrowth, and microtubule a G93A mutation. J Cell Biol. 1997;139(5):1307–15. organization. J Cell Biol. 2001;155(1):65–76. 68. Williamson TL, Cleveland DW. Slowing of axonal transport 48. Roy S, Zhang B, Lee VM-Y, Trojanowski JQ. Axonal is a very early event in the toxicity of ALS–linked SOD1 transport defects: a common theme in neurodegenerative mutants to motor neurons. Nat Neurosci. 1999;2(1):50–6. diseases. Acta Neuropathol. 2005;109(1):5–13. 69. Fanara P, Banerjee J, Hueck RV, Harper MR, Awada M, 49. Zhao Y, Mu X, Du G. Microtubule-stabilizing agents: New Turner H, et al. Stabilization of hyperdynamic microtubules drug discovery and cancer therapy. Pharmacol Ther. is neuroprotective in amyotrophic lateral sclerosis. J Biol 2016;162:134–43. Chem. 2007;282(32):23465–72. 50. Tsai RM, Miller Z, Koestler M, Rojas JC, Ljubenkov PA, 70. Kleele T, Marinković P, Williams PR, Stern S, Weigand EE, Rosen HJ, et al. Reactions to multiple ascending doses of Engerer P, et al. An assay to image neuronal microtubule the microtubule stabilizer TPI-287 in patients with Alzheimer dynamics in mice. Nat Commun. 2014;5(1):4827. Disease, progressive supranuclear palsy, and corticobasal 71. Huai J, Zhang Z. Structural properties and interaction syndrome: A randomized clinical trial. JAMA Neurol. partners of familial ALS-associated SOD1 mutants. Front 2020;77(2):215–24. Neurol. 2019;10:527. 51. Young JS, Hobbs JG, Bailes JE. The impact of traumatic 72. Cohen TJ, Lee VMY, Trojanowski JQ. TDP-43 functions brain injury on the aging brain. Curr Psychiatry Rep. and pathogenic mechanisms implicated in TDP-43 2016;18(9):81. proteinopathies. Trends Mol Med. 2011;17(11):659–67. 52. Saulle M, Greenwald BD. Chronic traumatic encephalopathy: 73. Magrané J, Cortez C, Gan W-B, Manfredi G. Abnormal

https://doi.org/10.37175/stemedicine.v2i6.81 8 MORTAL STEMedicine 2(6).e81. APR 2021

mitochondrial transport and morphology are common Rodriguiz RM, et al. Loss of deacetylation activity of pathological denominators in SOD1 and TDP43 ALS mouse Hdac6 affects emotional behavior in mice. PLOS ONE. models. Hum Mol Genet. 2014;23(6):1413–24. 2012;7(2):e30924. 74. Brunden KR, Yao Y, Potuzak JS, Ferrer NI, Ballatore C, 92. Liu R, Dang W, Du Y, Zhou Q, Jiao K, Liu Z. SIRT2 is James MJ, et al. The characterization of microtubule- involved in the modulation of depressive behaviors. Sci Rep. stabilizing drugs as possible therapeutic agents for 2015;5(1):8415. Alzheimer’s disease and related tauopathies. Pharmacol 93. Yang C, Wang G, Wang H, Liu Z, Wang X. Cytoskeletal Res. 2011;63(4):341–51. alterations in rat hippocampus following chronic 75. Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS, Hogan unpredictable mild stress and re-exposure to acute and A-ML, et al. Epothilone D improves microtubule density, chronic unpredictable mild stress. Behav Brain Res. axonal integrity, and cognition in a transgenic mouse model 2009;205(2):518–24. of tauopathy. J Neurosci. 2010;30(41):13861–6. 94. Lang B, Pu J, Hunter I, Liu M, Martin-Granados C, Reilly TJ, 76. Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak et al. Recurrent deletions of ULK4 in schizophrenia: a gene JS, et al. The microtubule-stabilizing agent, Epothilone D, crucial for neuritogenesis and neuronal motility. J Cell Sci. reduces axonal dysfunction, neurotoxicity, cognitive deficits, 2014;127(3):630–40. and Alzheimer-like pathology in an interventional study with 95. Coffey ET. Nuclear and cytosolic JNK signalling in neurons. aged tau transgenic mice. J Neurosci. 2012;32(11):3601–11. Nat Rev Neurosci. 2014;15(5):285–99. 77. Barten DM, Fanara P, Andorfer C, Hoque N, Wong PYA, 96. Alexander JE, Hunt DF, Lee MK, Shabanowitz J, Michel Husted KH, et al. Hyperdynamic microtubules, cognitive H, Berlin SC, et al. Characterization of posttranslational deficits, and pathology are improved in tau transgenic mice modifications in neuron-specific class III beta-tubulin with low doses of the microtubule-stabilizing agent BMS- by mass spectrometry. Proc Natl Acad Sci U S A. 241027. J Neurosci. 2012;32(21):7137–45. 1991;88(11):4685–9. 78. Killinger BA, Moszczynska A. Epothilone D prevents binge 97. Matten WT, Aubry M, West J, Maness PF. Tubulin is methamphetamine-mediated loss of striatal dopaminergic phosphorylated at tyrosine by pp60c-src in nerve growth markers. J Neurochem. 2016;136(3):510–25. cone membranes. J Cell Biol. 1990;111(5):1959–70. 79. Brunden KR, Gardner NM, James MJ, Yao Y, Trojanowski 98. Greenberger L.M., Loganzo F. (2008) Destabilizing Agents. JQ, Lee VM-Y, et al. MT-stabilizer, dictyostatin, exhibits In: Fojo T. (eds) The Role of Microtubules in Cell Biology, prolonged brain retention and activity: potential therapeutic Neurobiology, and Oncology. Cancer Drug Discovery and implications. ACS Med Chem Lett. 2013;4(9):886–9. Development. Humana Press. https://doi.org/10.1007/978-1- 80. Makani V, Zhang B, Han H, Yao Y, Lassalas P, Lou K, et 59745-336-3_10 al. Evaluation of the brain-penetrant microtubule-stabilizing 99. Corena-McLeod M, Walss-Bass C, Oliveros A, Villegas agent, dictyostatin, in the PS19 tau transgenic mouse model AG, Ceballos C, Charlesworth CM, et al. New model of of tauopathy. Acta Neuropathol Commun. 2016;4(1):106. action for mood stabilizers: phosphoproteome from rat pre- 81. Ballatore C, Brunden KR, Huryn DM, Trojanowski JQ, frontal cortex synaptoneurosomal preparations. PLOS ONE. Lee VM-Y, Smith AB. Microtubule stabilizing agents 2013;8(5):e52147. as potential treatment for Alzheimer’s Disease and 100. Janke C. The tubulin code: Molecular components, readout related neurodegenerative tauopathies. J Med Chem. mechanisms, and functions. J Cell Biol. 2014;206(4):461–72. 2012;55(21):8979–96. 101. Ikegami K, Heier RL, Taruishi M, Takagi H, Mukai M, 82. Brunden KR, Trojanowski JQ, Smith AB, Lee VM-Y, Shimma S, et al. Loss of α-tubulin polyglutamylation in Ballatore C. Microtubule-stabilizing agents as potential ROSA22 mice is associated with abnormal targeting of therapeutics for neurodegenerative disease. Bioorg Med KIF1A and modulated synaptic function. Proc Natl Acad Sci Chem. 2014;22(18):5040–9. U S A. 2007;104(9):3213–8. 83. Bianchi M, Shah AJ, Fone KCF, Atkins AR, Dawson LA, 102. Rajkumar AP, Christensen JH, Mattheisen M, Jacobsen I, Heidbreder CA, et al. Fluoxetine administration modulates Bache I, Pallesen J, et al. Analysis of t(9;17)(q33.2;q25.3) the cytoskeletal microtubular system in the rat hippocampus. chromosomal breakpoint regions and genetic association Synapse. 2009;63(4):359–64. reveals novel candidate genes for bipolar disorder. Bipolar 84. Piubelli C, Carboni L, Becchi S, Mathé AA, Domenici E. Disord. 2015;17(2):205–11. Regulation of cytoskeleton machinery, neurogenesis and 103. Fullston T, Gabb B, Callen D, Ullmann R, Woollatt E, Bain S, energy metabolism pathways in a rat gene-environment et al. Inherited balanced translocation t(9;17)(q33.2;q25.3) model of depression revealed by proteomic analysis. concomitant with a 16p13.1 duplication in a patient with Neuroscience. 2011;176:349–80. schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 85. Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, 2011;156(2):204–14. Huang JT-J, Griffin JL, et al. Mitochondrial dysfunction in 104. Fukushima N, Furuta D, Hidaka Y, Moriyama R, Tsujiuchi schizophrenia: evidence for compromised brain metabolism T. Post-translational modifications of tubulin in the nervous and oxidative stress. Mol Psychiatry. 2004;9(7):684–97, 643. system. J Neurochem. 2009;109(3):683–93. 86. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, 105. Bosch Grau M, Gonzalez Curto G, Rocha C, Magiera MM, Licznerski P, et al. Decreased expression of synapse-related Marques Sousa P, Giordano T, et al. Tubulin glycylases and genes and loss of synapses in major depressive disorder. glutamylases have distinct functions in stabilization and Nat Med. 2012;18(9):1413–7. motility of ependymal cilia. J Cell Biol. 2013;202(3):441–51. 87. Verhey KJ, Gaertig J. The tubulin code. Cell Cycle. 106. Marley A, Zastrow M von. A simple cell-based assay reveals 2007;6(17):2152–60. that diverse neuropsychiatric risk genes converge on 88. Magiera MM, Janke C. Post-translational modifications of primary cilia. PLOS ONE. 2012;7(10):e46647. tubulin. Curr Biol. 2014;24(9):R351–4. 107. Blanpied TA, Ehlers MD. Microanatomy of dendritic spines: 89. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon emerging principles of synaptic pathology in psychiatric and A, et al. HDAC6 is a microtubule-associated deacetylase. neurological disease. Biol Psychiatry. 2004;55(12):1121–7. Nature. 2002;417(6887):455–8. 108. Penzes P, Cahill ME, Jones KA, VanLeeuwen J-E, Woolfrey 90. Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, KM. Dendritic spine pathology in neuropsychiatric disorders. DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC Nat Neurosci. 2011;14(3):285–93. reproduces ketamine’s rapid and sustained antidepressant 109. Kaufmann WE, MacDonald SM, Altamura CR. Dendritic actions. Proc Natl Acad Sci U S A. 2015;112(26):8106–11. cytoskeletal protein expression in mental retardation: 91. Fukada M, Hanai A, Nakayama A, Suzuki T, Miyata N, an immunohistochemical study of the neocortex in Rett

https://doi.org/10.37175/stemedicine.v2i6.81 9 MORTAL STEMedicine 2(6).e81. APR 2021

syndrome. Cereb Cortex. 2000;10(10):992–1004. 123. Fontaine-Lenoir V, Chambraud B, Fellous A, David S, 110. Duman EA, Canli T. Influence of life stress, 5-HTTLPR Duchossoy Y, Baulieu E-E, et al. Microtubule-associated genotype, and SLC6A4 on gene expression protein 2 (MAP2) is a neurosteroid receptor. Proc Natl Acad and stress response in healthy Caucasian males. Biol Mood Sci U S A. 2006;103(12):4711–6. Anxiety Disord. 2015;5:2. 124. Cardounel A, Regelson W, Kalimi M. 111. Varidaki A, Mohammad H, Coffey ET. Chapter 5 - Molecular Dehydroepiandrosterone protects hippocampal neurons Mechanisms of Depression. In: Frodl T, curatore. Systems against neurotoxin-induced cell death: mechanism of Neuroscience in Depression [Internet]. San Diego: action2. Proc Soc Exp Biol Med. 1999;222(2):145–9. Academic Press; 2016 [citato 5 febbraio 2021]. pag. 143– 125. Marx CE, Jarskog LF, Lauder JM, Gilmore JH, Lieberman 78. Disponibile su: https://www.sciencedirect.com/science/ JA, Morrow AL. Neurosteroid modulation of embryonic article/pii/B9780128024560000054 neuronal survival in vitro following anoxia. Brain Res. 112. Gold PW. The organization of the stress system and 2000;871(1):104–12. its dysregulation in depressive illness. Mol Psychiatry. 126. Murakami K, Fellous A, Baulieu E-E, Robel P. Pregnenolone 2015;20(1):32–47. binds to microtubule-associated protein 2 and stimulates 113. Shelton MA, Newman JT, Gu H, Sampson AR, Fish KN, microtubule assembly. Proc Natl Acad Sci U S A. MacDonald ML, et al. Loss of microtubule-associated 2000;97(7):3579–84. protein 2 immunoreactivity linked to dendritic spine loss in 127. Roberts E, Bologa L, Flood JF, Smith GE. Effects schizophrenia. Biol Psychiatry. 2015;78(6):374–85. of dehydroepiandrosterone and its sulfate on brain 114. Harada A, Teng J, Takei Y, Oguchi K, Hirokawa N. MAP2 tissue in culture and on memory in mice. Brain Res. is required for dendrite elongation, PKA anchoring in 1987;406(1):357–62. dendrites, and proper PKA signal transduction. J Cell Biol. 128. Flood JF, Morley JE, Roberts E. Memory-enhancing effects in 2002;158(3):541–9. male mice of pregnenolone and steroids metabolically derived 115. Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ. from it. Proc Natl Acad Sci U S A. 1992;89(5):1567–71. Reduced spinophilin but not microtubule-associated protein 129. Karishma KK, Herbert J. Dehydroepiandrosterone (DHEA) 2 expression in the hippocampal formation in schizophrenia stimulates neurogenesis in the hippocampus of the rat, and mood disorders: molecular evidence for a pathology of promotes survival of newly formed neurons and prevents dendritic spines. Am J Psychiatry. 2004;161(10):1848–55. corticosterone-induced suppression. Eur J Neurosci. 116. Bosc C, Cronk JD, Pirollet F, Watterson DM, Haiech J, 2002;16(3):445–53. Job D, et al. Cloning, expression, and properties of the 130. Drago A, Crisafulli C, Sidoti A, Calabrò M, Serretti A. microtubule-stabilizing protein STOP. Proc Natl Acad Sci U The microtubule-associated molecular pathways may be S A. 1996;93(5):2125–30. genetically disrupted in patients with Bipolar Disorder. 117. Lefèvre J, Savarin P, Gans P, Hamon L, Clément M-J, David Insights from the molecular cascades. J Affect Disord. M-O, et al. Structural basis for the association of MAP6 2016;190:429–38. protein with microtubules and its regulation by calmodulin. J 131. Beurel E, Song L, Jope RS. Inhibition of glycogen synthase Biol Chem. 2013;288(34):24910–22. kinase-3 is necessary for the rapid antidepressant effect of 118. Fournet V, Schweitzer A, Chevarin C, Deloulme J-C, Hamon ketamine in mice. Mol Psychiatry. 2011;16(11):1068–70. M, Giros B, et al. The deletion of STOP/MAP6 protein in 132. Goold RG, Owen R, Gordon-Weeks PR. Glycogen synthase mice triggers highly altered mood and impaired cognitive kinase 3beta phosphorylation of microtubule-associated performances. J Neurochem. 2012;121(1):99–114. protein 1B regulates the stability of microtubules in growth 119. Gozes I. Microtubules, schizophrenia and cognitive cones. J Cell Sci. 1999;112(19):3373–84. behavior: preclinical development of davunetide (NAP) as a 133. Grimes CA, Jope RS. CREB DNA binding activity is inhibited peptide-drug candidate. Peptides. 2011;32(2):428–31. by glycogen synthase kinase-3β and facilitated by lithium. J 120. Shimizu H, Iwayama Y, Yamada K, Toyota T, Minabe Y, Neurochem. 2001;78(6):1219–32. Nakamura K, et al. Genetic and expression analyses of 134. Bélanger D, Farah CA, Nguyen MD, Lauzon M, Cornibert the STOP (MAP6) gene in schizophrenia. Schizophr Res. S, Leclerc N. The projection domain of MAP2b regulates 2006;84(2–3):244–52. microtubule protrusion and process formation in Sf9 cells. J 121. Plassart-Schiess E, Baulieu E-E. Neurosteroids: recent Cell Sci. 2002;115(7):1523–39. findings. Brain Res Brain Res Rev. 2001;37(1):133–40. 135. Cole AR. Glycogen synthase kinase 3 substrates in 122. Tsutsui K, Ukena K, Usui M, Sakamoto H, Takase M. Novel mood disorders and schizophrenia. The FEBS Journal. brain function: biosynthesis and actions of neurosteroids in 2013;280(21):5213–27. neurons. Neurosci Res. 2000;36(4):261–73.

https://doi.org/10.37175/stemedicine.v2i6.81 10